scholarly journals Structure and Membrane Targeting of the PDZD7 Harmonin Homology Domain (HHD) Associated With Hearing Loss

2021 ◽  
Vol 9 ◽  
Author(s):  
Lin Lin ◽  
Huang Wang ◽  
Decheng Ren ◽  
Yitian Xia ◽  
Guang He ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Vision Loss ◽  
Biochemical Characterization ◽  
Usher Syndrome ◽  
Pdz Domain ◽  
Binding Pocket ◽  
Binding Mode ◽  
Lipid Binding ◽  
Membrane Targeting ◽  
Pdz Domains

Usher syndrome (USH) is the leading cause of hereditary hearing–vision loss in humans. PDZ domain-containing 7 (PDZD7) has been reported to be a modifier of and contributor to USH. PDZD7 co-localizes with USH2 proteins in the inner ear hair cells and is essential for ankle-link formation and stereocilia development. PDZD7 contains three PDZ domains and a low-complexity region between the last two PDZ domains, which has been overlooked in the previous studies. Here we characterized a well-folded harmonin homology domain (HHD) from the middle region and solved the PDZD7 HHD structure at the resolution of 1.49 Å. PDZD7 HHD adopts the same five-helix fold as other HHDs found in Harmonin and Whirlin; however, in PDZD7 HHD, a unique α1N helix occupies the canonical binding pocket, suggesting a distinct binding mode. Moreover, we found that the PDZD7 HHD domain can bind lipid and mediate the localization of PDZD7 to the plasma membrane in HEK293T cells. Intriguingly, a hearing-loss mutation at the N-terminal extension region of the HHD can disrupt the lipid-binding ability of PDZD7 HHD, suggesting that HHD-mediated membrane targeting is required for the hearing process. This structural and biochemical characterization of the PDZD7 HHD region provides mechanistic explanations for human deafness-causing mutations in PDZD7. Furthermore, this structure will also facilitate biochemical and functional studies of other HHDs.

scholarly journals A Novel Computational Framework to Predict the Impact of a Point Mutation on PDZ Domain Classification

2018 ◽  
Author(s):  
Muhammad Moinuddin ◽  
Wasim Aftab ◽  
Adnan Memic
Keyword(s):  
Usher Syndrome ◽  
Pdz Domain ◽  
Point Mutations ◽  
Similarity Measures ◽  
Bigram Frequency ◽  
Computational Techniques ◽  
Pdz Domains ◽  
Computational Framework ◽  
Class 1 ◽  
The Impact

AbstractPDZ domains represent one of the most common protein homology regions playing key roles in several diseases. Point mutations (PM) in amino acid primary sequence of PDZ domains can alter domain functions by affecting for example, downstream phosphorylation, a pivotal process in biology. Our goal in this present study was to introduce a novel approach to investigate how point mutations within the Class 1, Class 2 and Class 1–2 PDZ domains could affect the changes in binding with their partner ligands and hence affect their classification. We focused on features in PDZ domains of various species including human, rat and mouse. However, our work represents a generic computational framework that could be used to analyze PM in any given PDZ sequence. We have adopted two different approaches to investigate the impact of PM. In the first approach, we have developed a statistical model using bigram frequencies of amino acids and employed six different similarity measures to contrast the bigram frequency distribution of a wild type sequence relevant to its point mutants. In the next approach, we developed a statistical method that incorporates the impact of bigram frequency history associated with each mutational site that we call history weighted conditional change in probabilities. In this PM study, we observed that the history weighted method performs best when compared to all other methods studied in terms of picking up sites in PDZ domain where a PM could flip the class. We anticipate that this method will present a step forward towards computational techniques unveiling PDZ domain point mutants that largely affect the protein-ligand binding, specificity and affinity. We hope that this and future studies could aid therapy in which PDZ mutations have been implicated as the main disease drivers such as the Usher syndrome.

scholarly journals Extensions of PSD-95/discs large/ZO-1 (PDZ) domains influence lipid binding and membrane targeting of syntenin-1

FEBS Letters ◽  
2012 ◽  
Vol 586 (10) ◽  
pp. 1445-1451 ◽  
Author(s):  
Anna Maria Wawrzyniak ◽  
Elke Vermeiren ◽  
Pascale Zimmermann ◽  
Ylva Ivarsson
Keyword(s):  
Lipid Binding ◽  
Membrane Targeting ◽  
Pdz Domains ◽  
Discs Large

scholarly journals Structure of Myo7b/USH1C complex suggests a general PDZ domain binding mode by MyTH4-FERM myosins

2017 ◽  
Vol 114 (19) ◽  
pp. E3776-E3785 ◽  
Author(s):  
Jianchao Li ◽  
Yunyun He ◽  
Meredith L. Weck ◽  
Qing Lu ◽  
Matthew J. Tyska ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Common Property ◽  
Pdz Domain ◽  
Binding Mode ◽  
Pdz Domains ◽  
Unconventional Myosin ◽  
Binding Partners ◽  
Interaction Mode ◽  
Similar Mode ◽  
And Function

Unconventional myosin 7a (Myo7a), myosin 7b (Myo7b), and myosin 15a (Myo15a) all contain MyTH4-FERM domains (myosin tail homology 4-band 4.1, ezrin, radixin, moesin; MF) in their cargo binding tails and are essential for the growth and function of microvilli and stereocilia. Numerous mutations have been identified in the MyTH4-FERM tandems of these myosins in patients suffering visual and hearing impairment. Although a number of MF domain binding partners have been identified, the molecular basis of interactions with the C-terminal MF domain (CMF) of these myosins remains poorly understood. Here we report the high-resolution crystal structure of Myo7b CMF in complex with the extended PDZ3 domain of USH1C (a.k.a., Harmonin), revealing a previously uncharacterized interaction mode both for MyTH4-FERM tandems and for PDZ domains. We predicted, based on the structure of the Myo7b CMF/USH1C PDZ3 complex, and verified that Myo7a CMF also binds to USH1C PDZ3 using a similar mode. The structure of the Myo7b CMF/USH1C PDZ complex provides mechanistic explanations for >20 deafness-causing mutations in Myo7a CMF. Taken together, these findings suggest that binding to PDZ domains, such as those from USH1C, PDZD7, and Whirlin, is a common property of CMFs of Myo7a, Myo7b, and Myo15a.

Structures and target recognition modes of PDZ domains: recurring themes and emerging pictures

2013 ◽  
Vol 455 (1) ◽  
pp. 1-14 ◽  
Author(s):  
Fei Ye ◽  
Mingjie Zhang
Keyword(s):  
Amino Acid ◽  
Pdz Domain ◽  
Binding Mode ◽  
Structural Features ◽  
Scaffold Proteins ◽  
Amino Acid Residues ◽  
Pdz Domains ◽  
Target Proteins ◽  
Protein Protein Interaction ◽  
Target Binding

PDZ domains are highly abundant protein–protein interaction modules and are often found in multidomain scaffold proteins. PDZ-domain-containing scaffold proteins regulate multiple biological processes, including trafficking and clustering receptors and ion channels at defined membrane regions, organizing and targeting signalling complexes at specific cellular compartments, interfacing cytoskeletal structures with membranes, and maintaining various cellular structures. PDZ domains, each with ~90-amino-acid residues folding into a highly similar structure, are best known to bind to short C-terminal tail peptides of their target proteins. A series of recent studies have revealed that, in addition to the canonical target-binding mode, many PDZ–target interactions involve amino acid residues beyond the regular PDZ domain fold, which we refer to as extensions. Such extension sequences often form an integral structural and functional unit with the attached PDZ domain, which is defined as a PDZ supramodule. Correspondingly, PDZ-domain-binding sequences from target proteins are frequently found to require extension sequences beyond canonical short C-terminal tail peptides. Formation of PDZ supramodules not only affords necessary binding specificities and affinities demanded by physiological functions of PDZ domain targets, but also provides regulatory switches to be built in the PDZ–target interactions. At the 20th anniversary of the discovery of PDZ domain proteins, we try to summarize structural features and target-binding properties of such PDZ supramodules emerging from studies in recent years.

scholarly journals The electrostatic allostery could be the trigger for the changes in dynamics for the PDZ domain of PICK1

2020 ◽  
Author(s):  
Amy O. Stevens ◽  
Yi He
Keyword(s):  
Surface Membrane ◽  
Pdz Domain ◽  
Binding Pocket ◽  
Pdz Domains ◽  
Interaction Domain ◽  
Bar Domain ◽  
Protein Protein Interaction ◽  
Loop Region ◽  
Key Factor ◽  
Dynamics Simulations

ABSTRACTThe PDZ domain is a highly abundant protein-protein interaction domain that exists in many signaling proteins, such as PICK1. Despite the highly conserved structure of the PDZ family, the PDZ family has an extremely low sequence identity, making each PDZ domain unique. PICK1 is the only protein in the human genome that is comprised of a PDZ domain and a BAR domain. PICK1 regulates surface membrane proteins and has been identified as an integral player in drug addiction. Like many PDZ-containing proteins, PICK1 is positively regulated by its PDZ domain and has thus drawn attention to be a potential drug target to curb the effects of substance abuse. The goal of this study is to use all-atom molecular dynamics simulations and the electrostatic analysis program, DelPhi, to better understand the unique interactions and dynamic changes in the PICK1 PDZ domain upon complex formation. Our results demonstrated that the PICK1 PDZ domain shares similar canonical PDZ-ligand hydrogen bonding networks and fluctuations of the carboxylate-binding loop to other PDZ domains. Furthermore, our results are unique to the PICK1 PDZ domain as we reveal that the binding of ligand opens up the binding pocket and, at the same time, reduces the fluctuations of both the central part of the binding pocket and the short loop region between the αA-helix and βC-strand. More importantly, the binding of ligand resulted in charge redistribution at the binding pocket region as well as the N- and C-termini of the PDZ domain that are not a part of the binding pocket. These results suggest that the electrostatic allostery resulted from ligand binding could be the key factor leading to the changes in dynamics which may be associated with the activation of PICK1. Based on these results, an effective drug to target PDZ domain must not only stably bind to the PICK1 PDZ domain but also prevent the electrostatic allostery of the PDZ domain.

scholarly journals A Thermodynamic Analysis of the Binding Specificity between Four Human PDZ Domains and Eight Host, Viral and Designed Ligands

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1071
Author(s):  
Eva S. Cobos ◽  
Ignacio E. Sánchez ◽  
Lucía B. Chemes ◽  
Jose C. Martinez ◽  
Javier Murciano-Calles
Keyword(s):  
Thermodynamic Analysis ◽  
Pdz Domain ◽  
Binding Specificity ◽  
Binding Mode ◽  
The Other ◽  
Cell Junctions ◽  
Pdz Domains ◽  
Host Interactions ◽  
Traditional Classification ◽  
Diverse Interactions

PDZ domains are binding modules mostly involved in cell signaling and cell–cell junctions. These domains are able to recognize a wide variety of natural targets and, among the PDZ partners, viruses have been discovered to interact with their host via a PDZ domain. With such an array of relevant and diverse interactions, PDZ binding specificity has been thoroughly studied and a traditional classification has grouped PDZ domains in three major specificity classes. In this work, we have selected four human PDZ domains covering the three canonical specificity-class binding mode and a set of their corresponding binders, including host/natural, viral and designed PDZ motifs. Through calorimetric techniques, we have covered the entire cross interactions between the selected PDZ domains and partners. The results indicate a rather basic specificity in each PDZ domain, with two of the domains that bind their cognate and some non-cognate ligands and the two other domains that basically bind their cognate partners. On the other hand, the host partners mostly bind their corresponding PDZ domain and, interestingly, the viral ligands are able to bind most of the studied PDZ domains, even those not previously described. Some viruses may have evolved to use of the ability of the PDZ fold to bind multiple targets, with resulting affinities for the virus–host interactions that are, in some cases, higher than for host–host interactions.

scholarly journals Identification of a Potential Founder Effect of a Novel PDZD7 Variant Involved in Moderate-to-Severe Sensorineural Hearing Loss in Koreans

2019 ◽  
Vol 20 (17) ◽  
pp. 4174 ◽  
Author(s):  
Sang-Yeon Lee ◽  
Jin Hee Han ◽  
Bong Jik Kim ◽  
Seung Ha Oh ◽  
Seungmin Lee ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Founder Effect ◽  
Hot Spot ◽  
Usher Syndrome ◽  
Pdz Domain ◽  
Missense Variant ◽  
Normal Hearing ◽  
Causative Gene ◽  
Str Markers ◽  
Korean Families

PDZD7, a PDZ domain-containing scaffold protein, is critical for the organization of Usher syndrome type 2 (USH2) interactome. Recently, biallelic PDZD7 variants have been associated with autosomal-recessive, non-syndromic hearing loss (ARNSHL). Indeed, we identified novel, likely pathogenic PDZD7 variants based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines from Korean families manifesting putative moderate-to-severe prelingual ARNSHL; these were c.490C>T (p.Arg164Trp), c.1669delC (p.Arg557Glyfs*13), and c.1526G>A (p.Gly509Glu), with p.Arg164Trp being a predominantly recurring variant. Given the recurring missense variant (p.Arg164Trp) from our cohort, we compared the genotyping data using six short tandem-repeat (STR) markers within or flanking PDZD7 between four probands carrying p.Arg164Trp and 81 normal-hearing controls. We observed an identical haplotype across three out of six STR genotyping markers exclusively shared by two unrelated hearing impaired probands but not by any of the 81 normal-hearing controls, suggesting a potential founder effect. However, STR genotyping, based on six STR markers, revealed various p.Arg164Trp-linked haplotypes shared by all of the affected subjects. In conclusion, PDZD7 can be an important causative gene for moderate to severe ARNSHL in Koreans. Moreover, at least some, if not all, p.Arg164Trp alleles in Koreans could exert a potential founder effect and arise from diverse haplotypes as a mutational hot spot.

Aetiologies of acquired deafblindness in a national sample

2018 ◽  
Vol 36 (2) ◽  
pp. 175-189 ◽  
Author(s):  
Jonas Henau Teglbjærg ◽  
Hanna Birkbak Hovaldt ◽  
Christine Lehane ◽  
Jesper Dammeyer
Keyword(s):  
Hearing Loss ◽  
Macular Degeneration ◽  
Vision Loss ◽  
Usher Syndrome ◽  
National Sample ◽  
Age Related Macular Degeneration ◽  
Age Related

The present study provides an overview of aetiologies and co-morbidities of acquired deafblindness in a Danish national sample of 514 individuals above 50 years of age identified with acquired deafblindness. Information was obtained from a survey and a register. The most frequent aetiology of vision loss was age-related macular degeneration (55.4%). The most frequent aetiology of hearing loss was presbycusis (53.7%). The most frequent aetiology of acquired deafblindness was the combination of age-related macular degeneration and presbycusis (41.5%). However, among the younger participants (50–59 years of age), Usher syndrome was the most common aetiology (62.5%). The aetiologies of acquired deafblindness are many and constituted by several different combinations of hearing and vision loss aetiologies. The most frequent aetiologies are age related.

Current Approaches to the Management of Usher Syndrome for the Clinician

2020 ◽  
Vol 5 (4) ◽  
pp. 907-916
Author(s):  
Alaa Koleilat ◽  
Lisa A. Schimmenti ◽  
Gayla L. Poling
Keyword(s):  
Health Care ◽  
Hearing Loss ◽  
Health Care Professionals ◽  
Vision Loss ◽  
Clinical Symptoms ◽  
Usher Syndrome ◽  
Speech Language Pathologist ◽  
Pathogenic Variants ◽  
Pediatric Populations ◽  
New Treatments

Purpose More than 460 million people suffer from disabling hearing loss worldwide, and about 50%–60% of hearing loss in infants are due to genetics. Usher syndrome is a genetic condition in which children are born deaf or hard of hearing and subsequently develop retinitis pigmentosa. It is the most common cause of deafness and blindness in pediatric populations, and pathogenic variants in 10 different genes are shown to be causative. The purpose of this review article is to advance the understanding of the clinical symptoms of an individual with Usher syndrome and highlight the latest research in the development of new treatments including gene therapy. The care and management of individuals with Usher syndrome require a team of multidisciplinary health care professionals, including an audiologist, a speech-language pathologist, an ophthalmologist, and a medical geneticist. We highlight the importance of early identification for better speech and developmental outcomes, specifically in pediatric individuals. Conclusion This review empowers audiologists to be aware of early signs of Usher syndrome as they are typically the first point of contact and provides important information for audiologists and other health care professionals involved in the care of individuals with hearing loss and vision loss.

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